scholarly journals Yeast Sphingolipid Phospholipase Gene ISC1 Regulates the Spindle Checkpoint by a CDC55-Dependent Mechanism

2020 ◽  
Vol 40 (12) ◽  
Author(s):  
Nabil Matmati ◽  
Bachar H. Hassan ◽  
Jihui Ren ◽  
Ashraf A. Shamssedine ◽  
Eunmi Jeong ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Regulation ◽  
Spindle Assembly Checkpoint ◽  
Synthetic Lethality ◽  
Spindle Checkpoint ◽  
Cellular Functions ◽  
Spindle Elongation ◽  
Synthetically Lethal ◽  
Cycle Regulation ◽  
Checkpoint Genes

ABSTRACT Defects in the spindle assembly checkpoint (SAC) can lead to aneuploidy and cancer. Sphingolipids have important roles in many cellular functions, including cell cycle regulation and apoptosis. However, the specific mechanisms and functions of sphingolipids in cell cycle regulation have not been elucidated. Using analysis of concordance for synthetic lethality for the yeast sphingolipid phospholipase ISC1, we identified two groups of genes. The first comprises genes involved in chromosome segregation and stability (CSM3, CTF4, YKE2, DCC1, and GIM4) as synthetically lethal with ISC1. The second group, to which ISC1 belongs, comprises genes involved in the spindle checkpoint (BUB1, MAD1, BIM1, and KAR3), and they all share the same synthetic lethality with the first group. We demonstrate that spindle checkpoint genes act upstream of Isc1, and their deletion phenocopies that of ISC1. Reciprocally, ISC1 deletion mutants were sensitive to benomyl, indicating a SAC defect. Similar to BUB1 deletion, ISC1 deletion prevents spindle elongation in hydroxyurea-treated cells. Mechanistically, PP2A-Cdc55 ceramide-activated phosphatase was found to act downstream of Isc1, thus coupling the spindle checkpoint genes and Isc1 to CDC55-mediated nuclear functions.

scholarly journals Targeting Non-Oncogene Addiction for Cancer Therapy

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 129
Author(s):  
Hae Ryung Chang ◽  
Eunyoung Jung ◽  
Soobin Cho ◽  
Young-Jun Jeon ◽  
Yonghwan Kim
Keyword(s):  
Cell Cycle ◽  
Dna Replication ◽  
Cancer Therapy ◽  
Cell Cycle Regulation ◽  
Synthetic Lethality ◽  
Current Knowledge ◽  
Cancer Therapies ◽  
Oncogene Addiction ◽  
Clinical Biomarkers ◽  
Cycle Regulation

While Next-Generation Sequencing (NGS) and technological advances have been useful in identifying genetic profiles of tumorigenesis, novel target proteins and various clinical biomarkers, cancer continues to be a major global health threat. DNA replication, DNA damage response (DDR) and repair, and cell cycle regulation continue to be essential systems in targeted cancer therapies. Although many genes involved in DDR are known to be tumor suppressor genes, cancer cells are often dependent and addicted to these genes, making them excellent therapeutic targets. In this review, genes implicated in DNA replication, DDR, DNA repair, cell cycle regulation are discussed with reference to peptide or small molecule inhibitors which may prove therapeutic in cancer patients. Additionally, the potential of utilizing novel synthetic lethal genes in these pathways is examined, providing possible new targets for future therapeutics. Specifically, we evaluate the potential of TONSL as a novel gene for targeted therapy. Although it is a scaffold protein with no known enzymatic activity, the strategy used for developing PCNA inhibitors can also be utilized to target TONSL. This review summarizes current knowledge on non-oncogene addiction, and the utilization of synthetic lethality for developing novel inhibitors targeting non-oncogenic addiction for cancer therapy.

scholarly journals PARP1 Deficiency Reduces Tumour Growth by Decreasing E2F1 Hyperactivation: A Novel Mechanism in the Treatment of Cancer

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2907
Author(s):  
Pablo Iglesias ◽  
Marcos Seoane ◽  
Irene Golán ◽  
Isabel Castro-Piedras ◽  
Máximo Fraga ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Synthetic Lethality ◽  
Wide Spectrum ◽  
Parp Inhibitors ◽  
Cellular Functions ◽  
Genetic Ablation ◽  
Protein Protein Interaction ◽  
Parp Activity ◽  
Cell Cycle Deregulation ◽  
Cycle Regulation

In recent years, poly (ADP-ribose) polymerase (PARP) inhibitors have been evaluated for treating homologous recombination-deficient tumours, taking advantage of synthetic lethality. However, increasing evidence indicates that PARP1 exert several cellular functions unrelated with their role on DNA repair, including function as a co-activator of transcription through protein-protein interaction with E2F1. Since the RB/E2F1 pathway is among the most frequently mutated in many tumour types, we investigated whether the absence of PARP activity could counteract the consequences of E2F1 hyperactivation. Our results demonstrate that genetic ablation of Parp1 extends the survival of Rb-null embryos, while genetic inactivation of Parp1 results in reduced development of pRb-dependent tumours. Our results demonstrate that PARP1 plays a key role as a transcriptional co-activator of the transcription factor E2F1, an important component of the cell cycle regulation. Considering that most oncogenic processes are associated with cell cycle deregulation, the disruption of this PARP1-E2F1 interaction could provide a new therapeutic target of great interest and a wide spectrum of indications.

scholarly journals Phosphorylation-Dependent Protein Interactions at the Spindle Midzone Mediate Cell Cycle Regulation of Spindle Elongation

2009 ◽  
Vol 17 (2) ◽  
pp. 244-256 ◽  
Author(s):  
Anton Khmelinskii ◽  
Johanna Roostalu ◽  
Helio Roque ◽  
Claude Antony ◽  
Elmar Schiebel
Keyword(s):  
Cell Cycle ◽  
Protein Interactions ◽  
Cell Cycle Regulation ◽  
Spindle Midzone ◽  
Dependent Protein ◽  
Spindle Elongation ◽  
Mediate Cell ◽  
Cycle Regulation

scholarly journals Cyclophosphamide Inhibits PI3K/AKT/mTOR Signaling Pathway in Mice Kidneys

Proceedings ◽  
2018 ◽  
Vol 2 (25) ◽  
pp. 1587 ◽  
Author(s):  
Gulsah Albayrak ◽  
Pinar Kilicarslan Sonmez ◽  
Damla Akogullari ◽  
Elgin Turkoz Uluer
Keyword(s):  
Cell Cycle ◽  
Protein Synthesis ◽  
Signaling Pathway ◽  
Cell Cycle Regulation ◽  
Kidney Tissue ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Cellular Functions ◽  
Cycle Regulation ◽  
Experimental Group

Cyclophosphamide (CTX), also known as cytophosphane among other, is a medication used as chemotherapy and to suppress the immune system. The PI3K/AKT/mTOR pathway is involved in the regulation of diverse cellular functions, including cell growth, protein synthesis, cell cycle regulation, glucose metabolism, and motility. In our study eight weeks old C57BL/6 female mice were divided into 3 groups as control (C), sham (S) and experimental group. The experimental group has been established with CTX treatment. No treatment was applied to the C group. The S group were given an equal amount of saline. CTX was administered intraperitoneally one every 2 days for 3 weeks; the first dose was 70 mg/kg, the ongoing doses were 30 mg/kg. At the end of 3 weeks mice were sacrificed and kidneys were taken for investigation. In order to show the effect of cyclophosphamide in kidney tissue, the tissues were stained via indirect immunohistochemistry with PI3K, AKT and mTOR primary antibodies. In our study, PI3K, AKT and mTOR expression levels were found to be significantly decreased in CTX-mediated mechanisms indicating that the mechanisms of CTX might involve in the inhibition of PI3K/AKT/mTOR signaling pathway.

scholarly journals DIPG-79. H3K27M INDUCES EPIGENETIC AND ONCOGENIC CHANGES THAT ARE PARTIALLY REVERSED BY SMALL MOLECULE AURORA KINASE B/C INHIBITION

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii302-iii303
Author(s):  
Hannah Chatwin ◽  
Rakeb Lemma ◽  
John DeSisto ◽  
Aaron Knox ◽  
Shelby Mestnik ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Regulation ◽  
Synthetic Lethality ◽  
Aurora Kinase ◽  
Therapeutic Modality ◽  
Rna Seq ◽  
Mesenchymal Transition ◽  
Aurora Kinase B ◽  
Cycle Regulation ◽  
H3k27m Mutation

Abstract Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric brain tumor with no curative treatments. Approximately 80% of DIPGs contain an H3K27M mutation. The implications of the mutation and how they may be targeted are not fully understood. We established an H3K27M effect-isolating model by transducing H3K27-wildtype lines (HSJD-GBM-001, normal human astrocytes) with lentiviral-packaged H3K27M. We characterized H3K27M-related changes through western blot, phenotypic assays, and RNA-seq. Drug screening of H3K27-wildtype and matched H3K27M-transduced lines was used to identify targets more effective with H3K27M present. Patient-derived pediatric glioblastoma and DIPG lines (BT-245, SU-DIPG-IV, HSJD-DIPG-007, SU-DIPG-XIII*, SF7761) were used for validation. We observed increased H3K27ac and decreased H3K27me3, as well as increased proliferative and migratory abilities, with the addition of H3K27M to H3K27-wildtype lines. RNA-seq showed downregulation of cell cycle regulation and upregulation of epithelial-mesenchymal transition. GSK1070916, an Aurora kinase B/C inhibitor, was isolated from a synthetic lethality screen with H3K27M. GSK1070916 showed strong efficacy in native H3K27M lines (IC50s=60nM-1250nM), superior to the Aurora kinase A inhibitor alisertib, to which all cell lines showed substantial resistance. Combination of both drugs was not synergistic. GSK1070916 treatment caused increased H3K27me3 and decreased H3S10ph and H3S28ph. GSK1070916 induced apoptosis and S-phase stall. The H3K27M mutation induces epigenetic, phenotypic, and cell cycle regulation changes resulting in relaxation of transcriptional controls and more aggressive growth. Aurora kinase B/C inhibition is a novel therapeutic modality for DIPG that appears capable of reversing some H3K27M-related epigenetic changes, inducing apoptosis, and repressing uncontrolled cellular division.

scholarly journals The Androgen and Progesterone Receptors Regulate Distinct Gene Networks and Cellular Functions in Decidualizing Endometrium

Endocrinology ◽  
2008 ◽  
Vol 149 (9) ◽  
pp. 4462-4474 ◽  
Author(s):  
Brianna Cloke ◽  
Kaisa Huhtinen ◽  
Luca Fusi ◽  
Takeshi Kajihara ◽  
Maria Yliheikkilä ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Gene Networks ◽  
Cell Cycle Regulation ◽  
Embryo Implantation ◽  
Fiber Formation ◽  
Cellular Functions ◽  
Endometrial Stromal Cells ◽  
Cytoskeletal Organization ◽  
Decidual Cells ◽  
Cycle Regulation

Progesterone is indispensable for differentiation of human endometrial stromal cells (HESCs) into decidual cells, a process that critically controls embryo implantation. We now show an important role for androgen receptor (AR) signaling in this differentiation process. Decreased posttranslational modification of the AR by small ubiquitin-like modifier (SUMO)-1 in decidualizing cells accounted for increased responsiveness to androgen. By combining small interfering RNA technology with genome-wide expression profiling, we found that AR and progesterone receptor (PR) regulate the expression of distinct decidual gene networks. Ingenuity pathway analysis implicated a preponderance of AR-induced genes in cytoskeletal organization and cell motility, whereas analysis of AR-repressed genes suggested involvement in cell cycle regulation. Functionally, AR depletion prevented differentiation-dependent stress fiber formation and promoted motility and proliferation of decidualizing cells. In comparison, PR depletion perturbed the expression of many more genes, underscoring the importance of this nuclear receptor in diverse cellular functions. However, several PR-dependent genes encode for signaling intermediates, and knockdown of PR, but not AR, compromised activation of WNT/β-catenin, TGFβ/SMAD, and signal transducer and activator of transcription (STAT) pathways in decidualizing cells. Thus, the nonredundant function of the AR in decidualizing HESCs, centered on cytoskeletal organization and cell cycle regulation, implies an important role for androgens in modulating fetal-maternal interactions. Moreover, we show that PR regulates HESC differentiation, at least in part, by reprogramming growth factor and cytokine signal transduction.

scholarly journals Dissection of yeast pleiotropic drug resistance regulation reveals links between cell cycle regulation and control of drug pump expression

2018 ◽  
Author(s):  
Jian Li ◽  
Kristen Kolberg ◽  
Ulrich Schlecht ◽  
Robert P. St.Onge ◽  
Ana Maria Aparicio ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Drug Resistance ◽  
High Throughput ◽  
Cell Cycle Regulation ◽  
Spindle Assembly Checkpoint ◽  
Control Mechanisms ◽  
Pleiotropic Drug Resistance ◽  
Biosensor System ◽  
Homozygous Diploid ◽  
Cycle Regulation

SummaryEukaryotes utilize a highly-conserved set of drug efflux transporters to confer pleiotropic drug resistance (PDR). Despite decades of effort interrogating this process, multiple aspects of the PDR process, in particular PDR regulation, remain mysterious. In order to interrogate the regulation of this critical process, we have developed a small-molecule responsive biosensor that couples PDR transcriptional induction to growth rate in Saccharomyces cerevisiae. We applied this system to genome-wide screens for potential PDR regulators using the homozygous diploid deletion collection. These screens identified and characterized a series of genes with significant but previously uncharacterized roles in the modulation of the yeast PDR in addition to recapitulating previously-known factors involved in PDR regulation. Furthermore, we demonstrate that disruptions of the mitotic spindle checkpoint assembly lead to elevated PDR response in response to exposure to certain compounds. These results not only establish our biosensor system as a viable tool to investigate PDR in high-throughput, but also uncovers novel control mechanisms governing PDR response and a previously uncharacterized link between this process and cell cycle regulation.SignificancePleiotropic drug resistance (PDR) is a conserved mechanism by which cells utilize membrane bound pumps to transport chemicals out of the cell. Here, we develop a growth-based biosensor system in yeast that enables high-throughput identification of factors that transcriptionally regulate PDR. Among the novel PDR regulators identified here, we show that spindle assembly checkpoint (SAC) proteins, which are important for cell cycle regulation, inhibit hyperactivation of PDR upon drug treatment. This result provides insights into PDR regulation, as well as potential targets for therapeutic intervention, particularly in chemoresistant cancers where the cell cycle regulation is often disrupted.

scholarly journals Genetic association of G2/M checkpoint genes with susceptibility to HIV-1 infection and AIDS progression in northern Chinese MSM population

2020 ◽  
Author(s):  
Jiawei Wu ◽  
Xuelong Zhang ◽  
Kaili Wang ◽  
Lidan Xu ◽  
Bangquan Liu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Genetic Variants ◽  
Cell Cycle Regulation ◽  
Northern China ◽  
Aids Progression ◽  
Northern Chinese ◽  
Key Genes ◽  
Cycle Regulation ◽  
Checkpoint Genes ◽  
Hiv 1

Abstract Background MSM has a high risk of HIV infection. Previous studies showed that the cell cycle regulation played an important role in HIV-1 infection, especially in G2/M checkpoint. The ATR, Chk1, Cdc25C and CDK1 are key genes in G2/M checkpoint. However, the association between the SNPs of these genes and susceptibility to HIV-1 infection and AIDS progression remains unknown. Results 42 tSNPs of G2/M checkpoint genes were genotyped to analyze the association between these tSNPs and susceptibility to HIV-1 infection and AIDS progression among MSM (529 HIV − 1 seropositive men and 529 HIV-1 seronegative men) in northern China. The results showed that rs34660854-A and rs75368165-A in ATR gene and rs3756766-A in Cdc25C gene could increase the risk of HIV-1 infection (P = 0.049, P = 0.020 and P = 0.010, respectively), and ATR rs75069062 and Chk1 rs10893405 were significantly associated with AIDS progression (P = 0.026 and P = 0.029, respectively). Besides, rs34660854 and rs75368165 in ATR gene, rs12576279 and rs540436 in Chk1 gene, rs3756766 in Cdc25C gene and rs139245206 in CDK1 gene were significantly associated with HIV-1 infection under different models (P < 0.05). Conclusions The genetic variants of G2/M checkpoint genes had a molecular impact on the genesis of HIV-1 infection and AIDS progression in northern Chinese MSM population.

scholarly journals PARP1 Deficiency Reduces Tumour Growth by Decreasing E2F1 Hyperactivation: A Novel Mechanism Beyond PARP Enzymatic Inhibition in the Treatment of Cancer

2020 ◽  
Author(s):  
Pablo Iglesias ◽  
Marcos Seoane ◽  
Irene Golán-Cancela ◽  
Isabel Castro-Piedras ◽  
Máximo Fraga ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Repair ◽  
Synthetic Lethality ◽  
Wide Spectrum ◽  
Parp Inhibitors ◽  
Cellular Functions ◽  
Genetic Ablation ◽  
Protein Protein Interaction ◽  
Cell Cycle Deregulation ◽  
Cycle Regulation

In recent years, poly (ADP-ribose) polymerase (PARP) inhibitors have heen evaluated for treating homologous recombination-deficient tumors, taking advantage of synthetic lethality. However, increasing evidence indicates that PARP proteins exert several cellular functions unrelated with their role on DNA repair, including function as a co-activators of transcription through protein-protein interaction with E2F1. Since the RB/E2F1 pathway is among the most frequently mutated in many tumours types, we investigated whether the absence of PARP activity could counteract the consequences of E2F1 hyperactivation. Our results demonstrate that genetic ablation of Parp1 extends the survival of Rb-null embryos, while genetic inactivation of Parp1 results in reduced development of pRb-dependent tumors. Our results demonstrate that PARP1 plays a key role as a transcriptional co-activator of the transcription factor E2F1, an important component of the cell cycle regulation. Furthermore, impairment of PARP results in a reduction of tumor growth, that is not depending of the activity of PARP on DNA repair. Considering that most oncogenic processes are associated with cell cycle deregulation, the disruption of this PARP1-E2F1 interaction could provide a new therapeutic target of great interest and a wide spectrum of indications.

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